18-nor-d-homo androstanes



United States Patent 0 3,194,831 IS-NOR-D-HOMO ANDRQSTANES Hans Reimann, Bloomfield, and Eugene P. Oliveto, Glen Ridge, N J., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Sept. 15, 1961, Ser. No. 138,272 14 Claims. (Cl. 260-488) This invention relates to novel IS-nor-D-homo steroids and to methods for their manufacture. In general this invention relates to l'l-keto-lS-nor-D-horno-l3(l7a)-dehydro androstanes having saturated A, B, and C rings, and having at Cll a hydroxyl group or estcr thereof. More specifically, this invention relates to llfi-hydroxy-U- keto-13(17a)-dehydro-l8-nor-D-homo 5a androstanes and 115 hydroxy l7-keto-13(l7a)-dehydro-18-nor-D- homo-SB-androstanes and ll-esters thereof which are valuable as therapeutics per se, or as intermediates in the preparation of other valuable steroids, and to methods for their manufacture.

Among the compounds included in our invention are 18-n0r-D-homo-l3(17a)-dehydrosteroids of the following structural Formula I:

wherein R is a member of the group consisting of H and an acyl radical of an acid of the group consisting of sulfonic acids and carboxylic acids having up to 12 carbon atoms; X is a member of the group consisting of H and halogen; Z is a member of the group consisting of keto; (H,BOR') and (H,aOR')R being a member of the group consisting of H and an acyl radical of an organic carboxylic acid having up to 12 carbon atoms.

The wavy line (MM) shown in the above formula signifies that the hydrogen bonded to the S-carbon may be present in an alpha (Sm-androstanes) or beta (5,8- androstanes) position.

Illustrative of the acyl groups which may be present at C3 and/or at Cll are lower alkanoates such as formate, acetate, propionate, butyrate, isobutyrate, valerate, isovalerate, pravalate, caproate (n-hexanoate), enanthate; sulfonates such as methanesulfonate and ptoluenesulfonate; aromatic acyl radicals of aryl carboxylic acids such as benzoate and toluate, as well as the acyl portions of dibasic acids such as succinate and phthalate.

Novel A, B, and C-ring saturated IIB-hydroxy-lS-nor- D-homo-5aand Sift-androstanes of this invention are typified by compounds such as 18-nor-D-homo-5a- 13(17a)-androstene-3fl,l1,6-diol-l7-one, the acetate and 3,11-diacetate esters thereof, 18-nor-D-homo-5B-l3(17a)- androstene-l1;3-ol-3,17-dione, 9a-fluoro-18-nor-D-homo- 5cx-l3(17a)-androstene-11,8-ol-3,17-dione and the 11-ptoluenesulfonic acid ester thereof; 9iz-bromo-l8-nor-D- homo-5a-13(17a)-androstene-3a,llfi-diol-l7-one and the 3-acetatc ester thereof and l8-nor-D-homo-5;3-l3(l7a)- androstene-SB,11 5-diol-17-one.

The novel 1S-nor-D'homo-13U7a)-dehydro-5a-andro stanes and Sfl-androstanes of Formula I are valuable therapeutic agents in that they are anti-androgenic agents. They are thus useful in the treatment of acne or in the alleviation of ailments such as enlargement of the prostate gland. While all the 18-nor-D-homo- 13(17a)dehydro-androstanes of Formula I are valuable 3,194,831 Patented July 13, 1965 anti-androgenic agents, the preferred species are the 18- nor-D-homo-5a-l3(17a)-androstenes and particularly 18- nor-D-homo-Sa-l3(17a)-androstene-3f3,1lfi-diol 17 one and esters thereof.

The l8-nor-D-homo steroids of our invention are conveniently manufactured by first preparing an ll-nitrite ester of an tlB-hydroxy-l7-lteto-Sa- (or 5B)-androstane which is saturated in the A-ring; and then subjecting the 1Iii-nitrite-l'i-keto-Sa- (or 5f3)-androstane to ultraviolet radiation which possesses a band of radiation corresponding to at least some of the absorption bands of the nitrite radical; and isolating the llfl-hydroxy-l7-keto-18-nor-D- l1on1o-5a-l3(17a)dehydroandrostene or 176-hydroXy-l7- keto l8-nor-D-homo-5fi-l3fl7a) dehydroandrostane thereby produced.

The llfl-acyloxy esters of Formula I, eg, the H5- acetate, llB-methanesulfonate, and the llB-benzoate, are then conveniently prepared from the corresponding 11;!- hydroxy-l8-nor-D-homo-androstanes thus produced and isolated, by utilizing conventional techniques such as reaction with an acid anhydride (e.g., acetic anhydride) or an acid halide (e.g., methanesulfonylchloride or benzoyl chloride) in pyridine.

Illustrative of our process is the following reaction sequence. Reaction of 11 S-hydroxy-S,8-androstane-3,17- dione with nitrosyl chloride in pyridine at 30 to --10" C. readily gives 1lfi-hydroxy-Sfl-androstane-3,17-dione llnitrite. The latter is irradiated with a Pyrex filtered 200 watt ultraviolet lamp, in a stream of nitrogen, in toluene at about 40 C. for about one hour. The solution is filtered from some insoluble material, concentrated and the product crystallized to give llfl-hydroxy-18-nor-D- homo-5&13(l7a)-androstene-3,l7-dione, which may be reacted with acetic anhydride in pyridine to give the corresponding ll-acylate, i.c.. 1lB-acetoxy-l8-nor-D-homo- 5;8-13 l7a)-androstene-3,17-dione.

It is thus apparent that the necessary intermediates in our process are ll-nitrite esters of androstanes of the following structural Formula II:

0 on i 1: (11) wherein X is a member of the group consisting of H and halogen, and Z is a member of the group consisting of keto; (H,BOR) and (H,uOR) wherein R' is a member of the group consisting of H and an acyl radical of a carboxylic acid having up to 12 carbon atoms.

The ll-nitrite-17-keto-5a-androstane and ll-nitrite-17- keto-Sflandrostane intermediates of our process are prepared by reacting a solution of the corresponding 11 3- hydroxy-l7-keto steroid in pyridine, dimethylformamide, ethyl acetate, or other non-polar solvent with a nitrosyl halide, preferably nitrosyl chloride. The nitrosyl chloride or bromide used may be added to the llfl-hydroxy steroid solution in the same solvent as that used to dissolve the llp-hydroxy steroid, or alternatively, it may be introduced as a gas into the steroidal alcohol solution. The formation of the lip-nitrite ester is usually rapid and generally complete within /2 hour. Nitrosyl chloride is added until there is a color change to orange-brown or other color which persists, at which time it can be assumed that the lie-nitrite has formed and the compound in solution is ready for separation and photolysis. The temperature at which the nitrite formation reactions are carried out range from usually 30 C. to +30 C. In general, when nitrosyl chloride is the reactant used, the reaction temperature is usually in the neighborhood from 20 C. to +10 C., and preferably at l5 C. to 5 C.

After completion of the formation of the llfi-nitrite ester, the nitrite is separated usually by adding water to the solution to precipitate the nitrite and by subsequent filtering followed by crystallization and recrystallization, if desired.

When preparing the ll-nitrite ester intermediates it is preferable to protect any free hydroxyl groups elsewhere in the molecule. Thus, for example, prior to reaction with nitrosyl chloride and subsequent irradiation, the 3-monoesters of 5a-androstane-3fi,11fi-diol-17-one, SIB-androstane 3,8,1 lfi-diol-l7-one, Sa-andrOstane-BuJ lfl-diol-17-one, and 5fi-androstane-3rx,l16-diol-17-one, e.g., the benzoate or acetate, are prepared by standard methods such as reaction of the corresponding S-hydroxy compound with an acid chloride or acid anhydride, e.g. benzoylchloride and acetic anhydride. Removal of the protective ester grouping is effected preferably after irradiation of the l1-nitrite-17-kcto steroid and isolation of the novel ll-hydroxy-l7-keto-l8- nor-D-homo-l3(l7a)-dehydro steroid thereby produced. Hydrolysis may be effected chemically by mild alkaline hydrolysis such as with methanolic sodium carbonate or, in the case of the acetate esters, by microbiological methods such as with F lavobncterz'um dehydrogenans (Rutgers Collection No. 130), utilizing procedures similar to those described in South African Patent No. 3,4-62/55. 5,8-androstane-3fl,1lr9-diol-17-one upon reaction with acctic anhydride and pyridine is converted to the corresponding 3-acetate ester which is reacted with nitrosyl chloride in pyridine as described herein to give 5,8-androstane-3;3, 11,B-diol 17-one 3-acetate ll-nitrite. ultraviolet light of a toluene solution of the aforementioned 3-acetate ll-nitrite ester, and isolation of the 18- nor-D-homo-l3( 17a) dehydrosteroid thereby formed yields l8-no1-D-homo-5;3-13( 17a)-androstene-3 ihllfi-diol- 17-one 3-acetate which may be subjected to the action of Flavobncterium dehydrogenans to give l8-nor-D-homo- 5fi-13(17a)-androstene-3[3,llfi-diol-l7-one.

When hydrolyzing via chemical techniques any ester groups present in an l8-nor-D-homo-l3(l7a)-dehydro- 5a: (or 5B)-androstane of our invention it is necessary to utilize only mild alkaline conditions if it is desired to obtain an 18-norD-homo-androstane of our invention possessing an ll-hydrosyl group. If hydrolysis is done under acid conditions or stronger basic conditions such as with perchloric acid or sodium hydroxide, respectively, simultaneous dehydration at C-ll will occur together with hydrolysis of any ester group present. Thus, for example, 5a-androstane-3fl,llfl-diol-l'Z-one B-acetate llnitrite upon photolysis according to the process described herein yields the novel 18-nor-D-homo-5a-l3(l7a)-androstene-lBJlfi-diol-l7-one 3-acetate. Hydrolysis of the aforementioned compound with sodium bicarbonate in methanol yields the corresponding 3-hydroxy compound of Formula I, whereas hydrolysis with pcrchloric acid or with potassium hydroxide in methanol yields the ll-clehydrosteroid, 18nor-D-homo-5ot-11,l3(17a) androstadiene-3r3-ol-l7-one. Our novel-l113-hydrony-18 nor D- homo steroids are thus useful as intermediates in the preparation of the corresponding ll-dehydrosteroids.

The A, B, and C-ring saturated 5c:- and SB-artdrostane I i-nitrite esters, after preparation and isolation as described above, are dissolved in a non-reactive solvent prior to being irradiated by ultraviolet light according to our process. The solvent chosen preferably has a high degree of transparency to the ultraviolet radiation within the specified band of nitrite absorption. Solvents which may be used for the photolysis of the nitrite include acetic acid, acetone, acetonitrile, benzene, carbon disulfide, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, dimethylether, dimethylformamidc, dioxane, ethyl Thus,

Irradiation with 4 acetate, Freon 113, heptane, methanol, ethanol, methylene chloride, and toluene. Of these benzene and toluene yield preferred results.

While the solvents used in the photolysis are ordinarily rater-free, a small amount of moisture in the solvent used for photolysis does not ordinariiy interfere with the progress of the ultraviolet activation and rearrangement of the nitrite in accordance with the present invention.

The ultraviolet radiation used to activate the nitrite radical is that band of radiant energy which corresponds to some or all of the ultraviolet absorption of the nitrite radical, and is from 3000 A. to 4400 A. The llnitrite ester thus irradiated and activated leaves the oxygen at Cll with concomitant abstraction of a hydrogen on the l8-carbon by the resulting Il-alkoxy group, together with splitting of the D-ring between C13 and (3-17 and ring reclosure resulting in a bond between original C-18 and C-l7 (new C17a and 17).

Radiant energy containing ultraviolet light in the range of 3000 to 4400 A. is conveniently supplied by a Hanovia high pressure mercury arc lamp with a Pyrex sleeve, while the nitrite to be reacted is contained in an ultraviolet transmitting vessel such as a water cooled Vycorimmersion well.

During the course of the photolysis of a llfi-nitrite ester of an androstane, a stream of nitrogen or other inert gas is generally bubbled through the solution (although not always necessary) to keep the nitrite solution protected by an inert atomsphere.

Our process whereby a steroidal l7-keto-liB-nitrite androstune is irradiated by ultraviolet light is usually carried out utilizing a 200 watt mercury lamp as an ultraviolet light source with the irradiated material being dissolved in benzene or toluene and kept under an atmosphere of nitrogen. The reaction is usually carried out at temperatures ranging from 1050 C. and preferably in the range of 18-40 C.

The photolysis of the nitrite ester which is carried on by irradiation with the selected band of ultraviolet radiation is monitored from time to time by ultraviolet or infrared spectrophotometry of an aliquot, and the reaction is complete when ultraviolet or infrared absorption spectra lack the characteristic spectra of the nitrite radical.

By our process of photolyzing an ll-nitrite ester of an A-ring saturated-l7-keto-5a(or 5fl)-androstane, there is obtained a mixture of products (a major portion being an lS-nor-D-homo-13(l7a)-dehydro-5a(or 56) androstane of formula I) which are separable by filtration, by partition chromatographic techniques, by fractional crystallization, or by a combinaton of these techniques.

Our novel compounds may be crystallized from organic solvents such as ethyl acetate, acetone, acetone-hexane, methylene chloride, methylene chloride-ether and the like, or are chromatographed on Florisil using eluting solvents and solvent mixtures such as hexane, ether-hexane, ether, ether-methylene chloride, methylene chloride, methylene chloride-acetone and the like. Alternatively, our novel 18-nor-D-homo-5u(or 5,6)-13(l7a)-androstenes may be isolated using a partition chromatographic system on Chromosorb, such as ligroin-propylene glycol, toluenepropylene glycol, and the like. When chromatographic techniques are employed, fractions are monitored by infrared and ultraviolet spectroscopy to determine the zones containing the desired 11;3-hydroxy-l8-nor-D homo-Seder 5;3)-13(17a)-androstenes.

The necessary starting compounds in the process of preparing the novel 18-nor-D-homo steroids of Formula I are 1ltd-hydroxy-l7-keto-5a-androstanes and 11,8-hy droxy-l7-keto-5B-androstanes of Formula II. Some of these starting compounds are known, such as Six-androstane 3fi,1l(3-diol-l7-one, 5a-androstane3a,1lB-diol-l'7- one, 5B-androstane-3a,11,8-diol-17-onc, and the B-acetate esters of the foregoing.

Other 115 hydroxy-l'i-keto-Sfland SID-andmstane starting steroids may be prepared from known 11,6,17or,21-

trihydroxy--keto-5aand Sfi-pregnanes by the oxidative degradation of the C-17 side chain utilizing sodium bismuthate. Thus, Sfl-pregnane-l15,17 x,21-triol-3,20-dione 2l-acetate is hydrolyzed to the corresponding 2lalcohol by means of potassium bicarbonate in methanol, for example, and the resulting SB-pregnane-l1fi,l7 x,2l-triol- 3,20-dione is reacted with sodium bismuthate in aqueous acetic acid to yield the starting compound, SB-androstane- 1lfi-ol-3,17-dione. Other typical 1l,B,l'/'u,2l-trihydroxy- 3,20-diketo-5uand Sfi-pregnanes and their 2l-acetate esters which, after hydrolysis of the 2l-esters, may be degraded to form the corresponding 17-keto androstanes, are Son-androstane-l1 3,17a,2l-triol-3,20-dione 21-acetate and the 9a-fiuoro, 9a-chloro, and Qix-bromo derivatives thereof, from which are derived the starting compounds ia-androstane-l1/8-ol-3,l7dione, ga-fiLlOlD-Scc-HHClIOSiBflB- 115-ol-3,l7-dione, 9a-chloro-5aand rostane-1lB-ol-3J7- dione and 9a-brom0-5a-androstanti-l1B-ol-3,l7-dione, respectively.

Alternatively, 1le-hydroxy-l7-keto-5a(and 5fi)-androstane starting compounds may be conveniently prepared from the corresponding 11-desoxy-17-keto-5e(or 5B)- androstanes by hydroxylating microbiologically at (1-11 with the aid of a microorganism such as Curvularia ILmata (N.R.R.L. 2380) using procedures analogous to those described in US. Patent No. 2,658,023.

Introduction of a 9a-halogen group into a 11 fl-hydroxy- 17-keto-5a-androstane or Sfl-androstane may be effected by dehydrating an llfi-hydroxy-androstane such as 5e4- androstane-3,8,l lB-diol-l7-one B-acetate or Sfi-androstane- 11B-ol-3,l7-dione, for example, with an alkyl or arylsulfonyl chloride (e.g., methanesulfonyl chloride) in an alkaline organic medium such as in pyridine to effect the production of the corresponding 9(1l)-dehydro-intermediate, e.g., 5ot-9(11)-androstene-3fi-ol-17-one 3-acetate and 5fi-9(11)-androstene-3,l7-dione, respectively. Placement of a halogen, and preferably bromine at this point in the procedure, at the 9ix-carbon position is accomplished by conventional means, such as by reacting the 9(11)-dehydrosteroid with hypobromous acid, which can be prepared in situ from the reaction of N-bromoacetamide and aqueous perchloric acid, yielding directly the corresponding 9ix-bromo- 5a-androstane-3p,l1,8-diol-17- one 3-acetate and 9a-br0mo-11.fi-hydroxy-SB-androstane-3, 17-dione respectively. Other 9a-halogeno derivatives are obtained from 9a-bromo-1IB-hydroxy steroids such as the aforementioned, by refluxing the 9a-llB-bromohydrins with mild alkali, such as sodium acetate in methanol, to form the corresponding 9fi,l1B-oxido derivatives, e.g., 9,3,11fl-oxido-Sa-androstane-Iifl-ol-l7-one S-acetate 96,115 oxido-SB-androstane-3,17dione. These latter compounds are then reacted with hydrogen fluoride in chloroform with or without ethanol and/or tetrahydrofuran to form fiuorohydrins, e.g., 9a-flLl01'0-llfi-l1YdIOXY- 5a-androstane-3fi-ol-17-one B-acetate, and 9tx-fluoro-1l,8- hydroxy-5B-androstane-3,l7-dione. Similarly, the substitution of anhydrous hydrogen chloride for hydrogen fluoride in this reaction results in the production of the corresponding 9a-chloroderivatives.

The 9ot-halogeno compounds thus prepared may then be esterified at C-ll to the nitrite ester and irradiated with ultraviolet light within the range of 3000 to 5000 A. according to our invention to obtain the 9ot-halogeno-18- nor-D-hom-o-l7-keto-l3(17a)-dehydro-steroids of this invention. For example, Qa-tluoro-llfl-hydroxy-Sfi-androstane-3,17-dione and 9a-fiuoro-11fi-hydroxy-5a-androstane-3B-ol-17-one 3-acetate upon reaction with nitrosyl chloride in the manner described herein yield the corresponding llfi-nitrite esters which upon irradiation by ultraviolet light while in solution, in a non-polar solvent such as toluene or benzene, and subsequent isolation of the novel compounds of our invention yield 9a-fluoro- 18nor-D-homo-5/3-13(17a)-androstene 115 ol 3,l7- dione, and 9a-fluoro-l8-nor-D-homo-5a-l3(17a)-androstene-3fl,l1fi-diol 17-one B-acetate respectively.

and

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The following are examples which illustrate our invention. They are not to be construed as limiting the scope of our invention, our invention being limited by the appended claims only.

EXAMPLE 1 A. 5a-androstane-3fi,IIB-a'iol-l7 one 3 acetate 11- nirrite.-To a solution of 1.075 g. of Sa-androstane- 3,8,1lfi-diol-17-one 3-acetate in 10 ml. of dry pyridine chilled to C. is added dropwise a chilled saturated solution of nitrosyl chloride in pyridine until a reaction mixture has a definite orange color. During the addition, the reaction solution is allowed to warm to l0 C. and is stirred at this temperature for one-half hour after the addition is complete. The reaction mixture is poured into ice water. A solid separates which is filtered, washed with water and dried to give 5a-androstane-3B,llfi-dioll7-one 3-acetate ll-nitrite, M.P. 136138 C., [011 (chloroform) +69 A Nujol 5.74, 5.78, 6.10, 6.21, 8.1;.

B. I8-nor-D-h0m0 5u-13U7a)-andr0stene-3;9,I1fl-diol- ]7Oite'3lCffilC.-A solution of 1 g. of iwandrostane- 3,6,lle-diol-l7-one B-acetate ll-nitrite in 200 ml. of toluone under a blanket of nitrogen is irradiated for one hour at C. with a 200 watt mercury lamp provided with a Pyrex filter. The irradiated solution is filtered and the insoluble residue discarded. The filtrate is concentrated in vacuo to a residue which is chromatographed on Florisil, the column being eluted with an ether-hexane mixture. The fractions exhibiting ultraviolet absorption (as determined by the spot test technique) are combined and crystallized from ether to give l8-I10f-D-l10l1lO-5a- 13( 17a) androstene 35,11/3-diol-l7-one 3-acetate, M.P. 150-155 C.

AHQB 242 Ii'lp( 6 14,000) ltNujol 2.90, 5.75, 5.99, 6.12, 8.0 EXAMPLE 2 1 8-nor-D-hom0-5 ,8-1 3 (1 7a -arzdr0stene-3a,1 l 5- diol-17-0ne 3-acetate A. 5,B-andr0stanc-3q,IIfi-dioI-I7-0ne .i-acetate 1 I -m'- trite.In the manner of Example 1A, 5fl-androstanc-3a, 11 fl-diol-l7-one 3-acetate is reacted with nitrosyl chloride in pyridine and the resultant product isolated and dried to give 5 3-androstane-3a,llfl-diol-17-one 3-acetate ll-nitrite.

B. I8-n0r-D-h0m0-5t3-I3(1 7a)-androstene-3a,l Ifl-diol- J7-0ne 3acemte.ln the manner described in Example 1B, -androstane-3a,l1;3-dioll7-one 3-acetate ll-nitrite in toluene is irradiated with a 2 00 watt mercury lamp and the resultant product isolated and purified to give l8-nor- D-homo-Sfl-B 17a)-androstene-3a,1 lB-diol-l7-one 3-acetate.

EXAMPLE 3 A. 5,8-pregnane-I1B,I7a,21-tri0l-3,20-di0ne.A mixture of SB-pregnane-l1,8,17e,21-triol-3,20-dione Zl-acetate and 1.1 equivalents of potassium bicarbonate in aqueous methanol is refluxed under nitrogen for 30 minutes, concentrated in vacuo to about half the original total volume, then diluted with water. The resultant precipitate is filtered and dried to give Sdpregnane-l1 8,17a,2l-triol- 3,20 -dione.

B. 5 p-Androsmne-l I 5-0l-3J7-di0na-To a solution of 5 g. of SS-pregnane-l15,17111l-triol-3.20-dione in 300 ml. of 50 percent aqueous acetic acid is added 25 g. of sodium bismuthate and the mixture is stirred for 30 minutes at t o C. The reaction mixture is filtered and the filtrate diluted with Water and extracted wtih methylene chloride. The organic extracts are combined and concentrated to a volume of about 15 ml. The concentrated solution is then filtered through a column of Florisil, eluting with ether. The eluates are combined and concentrated to a residue to give 5,8androstanc-11fi-ol-3,l7-dione.

A. 5a-andr0stane-11fl-0l-3J 7-di0ne and 9.1 halogena- Son-HrldfOStdllG-I 1 6-0l-3,I7-dione. Sa-pregnane-l 15,17, 2l-trio1-3,20-dione 2l-acetate, 9a-fiuoro-5a-pregnane-l15,

17a,Zl-triol-3,20-dione ZI-acetate, 9a-chloro-5a-pregnanell3,17u,2l-triol-3,20-dione 2l-acetate, and 9a-blOrllD-5rxpregnane-ll 3,1711)l-triol-3,20-dione Zl-acetate are each reacted with 1.1 equivalents of potassium bicarbonate in aqueous methanol in the manner described in Example 3A and each of the resultant products isolated to give respectively, 5a-pregnane-l1,8,l7a,2l-triol-3,20dione, 9a-fiuoro- Sa-pregnane-l1 8,17a,2l-triol-3,20-dione, 9a chloro 5apregnane-ll,5,17a,2l-triol-3,20-dione, and 9a bromo 5o;- pregnane-l1,3,17a,2l-triol-3,20-dione.

Utilizing the procedure similar to that described in with sodium bismuthate in aqueous acetic acid and each resultant product isolated and purified to give respectively, Sa-androstane-llB-o1-3,l7-dione, 9a-fiuoro-5a-androstanellfl-ol-3,l7-dione, 9a-chloro-5a-androstane-l1B ol 3,17- dione, and 9a-bromo-5a-androstane-l 15-ol-3,l7-dione.

B. 5a-andr0stanc-1Iii-013,1 7-di0ne JJ-nizrite and 9e.- H

halogeno-Sa-androstane-l 1 801-3.] 7-dz'one.-In the manner described in Example 1A, Soc-Hildl'OSiflnE-l1{3-0l-3,17 dione is reacted with nitrosyl chloride in pyridine to give 5a-androstane-11 3ol-3,17-dione ll-nitrite.

In a similar manner, 9u-fiuoro-5u-androstane-ll,8-0l- 3.17-dione, Qa-chIorQ-Sa-androstane-l LB-ol 3,17 dione, and 9a-bromo-5wandrostane-llB-ol-3,l7-dione are each reacted with nitrosyl chloride to give respectively 90:- fluOro-Sa-androstane-IlB-o1-3,17-dione 11 nitrite, 9o:-

chloro-5wandrostane-1lB-ol-3,l7-dione ll-nitrite, and 9abromo-S wandrostane-l lfi-ol-3, l 7-dione ll-nitrite.

C. l8-nor-D-homo-5a-l3(l7a)-aridrostcne-l 15-013,- dione and 9a-halogcno-l 8-n0r-D-h0-m0-5ct-13 1 7a -andrstcne llfi-ol-3J7-di0ne. a androstane ll,9-ol-3,l7- 'dione ll-nitrite in toluene is irradiated with a 200 watt mercury lamp in the manner of Example 1B. The re sultant product is isolated and purified to give lS-nor-D- homo-5a-l3 l7a)-androstcne-l lfl-ol-3,l7-dione.

Similarly, 9a-fluoro-5a-androstane-l lB-ol 3,17 dione ll-nitrite, 9a-chloro-5a-androstane-ll5-ol-3,17-dione llnitrite, and 9wbromo-5a-androstane-llB-ol-3,l7-dione llnitrite, are each irradiated with a 200 watt mercury lamp while in a toluene solution and the resultant product isolated to give respectively 9a-fiuOtO-l3-Il0T-D-l10mO-5a- 13 l7a)-ano'rostene-l l5-ol-3,l7-dior1e, 9oc-Chl0I0-l8-1'IOY- D-homo-5a-l3(l7a)-androstene-l l6 ol 3,17-dione, and 9a-bromo-l8-nor-D-horno-5a-l3 l7a)-androstene-l lB-ol- 3,17-di0ne.

EXAMPLE 5 3-0xygenated-9a-halogeno-IIp-hydr0xy-17-ket0 5m and 5 fi-GHdTOSldHGS A. 3-0xygenated-17-ket0-9(11)-dehydr0-5aand 5 B-andr0sranes.A solution of 5 g. of Sa-androstane-I'adllfidiol-17-oue 3-acetate in 100 ml. of pyridine is chilled to 0 C. and a solution of ml. of methanesulfonyl chloride in ml. of chloroform is added dropwise. The mixture is allowed to stand in the ice box for 100 hours, then a little ice is added and the solution diluted with chloroform. The organic solution is washed with water, 5 percent hydrochloric acid, 5 percent aqueous sodium bicarbonate, and again with water. The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to a residue which is crystallized twice from acetone-hexane to give 5a-9(l1)-andr0stene-3 3-ol-17-one 3-acetate.

In a similar manner 5fiandrostane-3a,llfi-ol-17one Z-acetate and Sfi-androstane-l1Bdiol-3,l7-dione are each reacted with methanesulfonyl chloride in pyridine and the resultant product isolated and purified to give respectively 5;8-9(11)-androstene-3a-ol-l7-one 3-acetate and 513- 9(l1)-androstene-3,17-dione.

B. 3-0xygenaed-9d-br0m0-1Ifl-hydr0xy-17-ket0-5aand 55-andr0stanes.--To a solution of 0.150 g. of Sd-9(11)- androstene-3p-ol-17-one 3-acetate in 20 ml. of dioxane (which has been purified by refluxing over sodium followed by distillation) and 2 ml. of water is added 0.07 g. of N-bromoacetamide and 1 ml. of 1.5 N perchloric acid. The mixture is allowed to stand for 2 hours, then a solution of 0.2 g. of sodium sulfite in 2 ml. of water is added and the mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over magnesium sulfate and evaporated to a residue which is crystallized from acetone to give 9cx-bT0mO-5onandrostane-35,1 lB-diol-17-one 3-acetate.

In a similar manner 5fi-9(ll)-androstene-3a-ol-l7-one 3acetate and 5fi-9(ll)-androstene-3,l7-dione are each reacted With N-bromoacetamide and perchloric acid to yield respectively, 9a-bromo-5B-androstane-3a,llfi-dioll7-one 3-acetate and 9a-bromo-5B-androstane-llp-ol- 3,17-dione.

C. 3-OXygCIICIIEd-9fl,IIfl-OXidO-I7 ktO-tand -mdr0s!anes.-T0 0.5 g. of 9a-bromo-5a-androstane-3fi,11pdiol-l7-one 3-acetate in 30 ml. of acetone is added 0.3 g. of potassium acetate. The reaction mixture is refluxed for 6 hours, then the acetone is distilled and water is added to the resultant residue. A solid separates which is filtered and crystallized from methanol-water to give Set-androstane-9[3,l 1fi-oxido-3fi-ol-l7-one 3-acetate.

In a similar manner 9a-bromo-SB-androstane-M,11,6- diol-l7-one 3-acetate and 9a-bromo-5p-androstane-l1B- 0l-3,l7-dione are each reacted with potassium acetate in acetone to give, respectively, 9&1lfi-oxido-Sfl-androstane- 3ct-Ol-l7-Gl'l8 3-acetate and 93,1lfi-oxido-SB-androstane- 3,17-dione.

D. 3-0xygenated-9a fluoro 11B hydr0xy-17-ket0-5aand 5/i-andr0stnnes.To 3.5 g. of hydrogen fluoride in 20 ml. of chloroform and 0.6 ml. of tetrahydrofuran at -l0 C. is added 1.0 g. of 9 3,1lfi-oxido-M-androstane- 3Q-ol-l7-one 3-acetate. The reaction mixture is kept at --l0 C. for 3 hours, then poured into aqueous sodium carbonate solution. The organic solvent layer is separated from the water and evaporated to a residue which is crystallized from methanol to give 9a-fluoro-5a-androstane-3;3,l l ,8-diol-17-one 3-acetate.

In a similar manner, 95,11fl-oxido-5/3-androstane-3a-oll7-one 3-acetate and 9,8,1lB-oxido-S/i-androstane-S,l7- dione are each reacted with hydrogen fluoride in chloroform and tetrahydrofuran to give, respectively, 9oc-fil10l0 5B-androstane-3a,llfi-diol-17-one 3-acetate and Qu-fluoro- 5 fl-androstaned l {3-ol-3, 17-dione.

In a similar manner, 9,3,1lp-oxido-Stit-androstane-Saol-17-one 3-acetate and 9B,l1fi-oxido-5fl-androstane-3,17- dione are each reacted with hydrogen chloride in chloroform to give respectively 9a-chloro5;8-androstane-3a,1lfidiol-17-one S-acetate and Qa-ChlOIO-Sfi-fil'ldl'OSliltlC-l113-01- 3,17-dione.

EXAMPLE 6 A. II-nitrl'te esters of 3-0xygenated-9ct-halogeno-J1,8- hydr0xy-17-kcr0-5aand 5fi-clndrosmnes.ln the manner described in Example 1A, 9a-fluoro-5a-androslane-3,8,l1(3- diol-l7-one 3-acetate (prepared as described in Example 51)) is reacted with nitrosyl chloride in pyridine and the resultant product isolated to give 9a-fiuorQ-Sa-androstanc- 3,8,11,8-diol-17-one 3-acetate ll-nitrite.

In a similar manner, 9a-fluoro-5fi-androstane-3 1,1l5- diol-17-one 3-acetate, 9a fluoro 55 androstane-l 1 3-01- 3,17-dione, 9a-bromo-5a-androstane-3B,11,6 diol 17-one 3-acetate, 9tx-bl'OZYLO-5fi-2ll'ldf08llill'lfi-3t1,llfi-CllOl-l7-Oll6 3- acetate, 9m-bromo-5fi-androstane-1118 ol 3,17-dione, 91xchloro-Sa-androstane-3t8,11,8 diol 17 one S-acetate, 9n:- chloro-SB-androstane-h,11 8-diol-17-one S-acetate and 9achloro-SB-androslane-l1fi-ol-3,l7-dione are each reacted with nitrosyl chloride in pyridine to give respectively 9afluoro-Sfi-androstane-hdlfi-diol-17-one 3-acetate 11-nitrite, 9a-fluoro-5B-androstane-l1fl-ol-3,17-dione ll-nitrite, 9a-bromo-5a-androstane-3,3,11B-diol-17-one 3-acetate 11- nitrite, 9a-bromo-5fi-androstane-3a,l1,8 diol 17 one 3- acetate ll-nitrite, 9a-bromo 513 androstane-11B-ol-3,17- dione ll-nitrite, 9a-chloro-5a-androstane-3B,1lu-diol-l7- one 3-acetate ll-nitrite, 9a-chIOro-Sti-androstane-3u,115- diol-l7-one 3-acetate ll-nitrite and 9a-chloro5,8-androstane-11,8-ol-3,17-dione ll-nitrite.

B. 3-0xygenated-9a hul geno 11B hydr0xy-17-kez0- 13(17a)-dchydr0-5aand 5f3-andr0stanes.-In a manner similar to that described in Example 1B 9ot-ilL101'O-5a-fll1- drostane-3B,11 8-diol-17-one 3-acetate ll-nitrite in toluene is irradiated with a 200 watt mercury lamp and the resultant product isolated and purified to give 9a-llLl0l0-18- nor-D-homo-5a-13 17a) -androstene-3B, 1 lfi-diol-17-one 3- acetate.

In a similar manner, 9a-fiuoro-5fl-androstane-3 1,11;?-

diol-17-one 3-acetate ll-nitrite, 9a-fiuoro-5fl-androstanet 11B-ol-3,17-dione ll-nitrite, 9a-bromo-5a-androstane- 3B,11 3-diol-17-one 3-acetate ll-nitrite, Qa-brOmo-SB- androstane-3a,llfi-diol-17-one 3-acetate ll-nitrite, 9abromo-Sfi-androstane-llB-ol-3,17-dione 11 nitrite, 9achloro-5a-androstane-3B,1lfi-diol-l7-one 3-acetate ll-nitrite, 9a chloro Sfi-androstane 30,1l;3 diol 17 one 3-acetate ll-nitrite, and 9a-chloro-5Bandrostane-liii-ol- 3,17-dione ll-nitrite each in toluene solution are irradiated with a ZOO-watt mercury lamp and the resultant products isolated and purified to give respectively, 9:1- i

fluoro-l8-nor-Dhomo-55l3(17a) androstene 30,1lfidiol-l7-one S-acetate, 9a-fluoro 18 nor D homo 5(3- 13(17a)-androstene 11B ol 3,17-dione, 9a-bromo-18- nor-D-hom0-5u-13(17a)-androstene-3,8,1lfi diol 17-one B-acetate, 9a-bromo-18-nor-D-homo 5p 13( l7a)-androstene-3u,11;3-diol-17-one 3-acetate, 9a-bromo-l8-r1or-D- hom0-5fi-l3(l7a) androstene 11,8 ol 3,17-dione, 9achloro-lS-nor-D-homo 5a 13 17a) androstene-3;8,11- diol-17-one S-acetate, 9a-chloro 18 nor-D homo 5fi- 13 17a)-androstene-3 0;,1118 diol 17 one 3-acetate, and 9a-chloro-IB-nor-D-homo-Sli-l3(1721) androstene 11B- ol-3,17-dione.

EXAMPLE 7 3a-ace!0xy-9ot-lmI0geno-1 1 B-hydroxy-l 7-ket0- 5 a-androstane A. 5a-9(1I)-andr0stene-3a 01- J7 one 3-acetate.-In the manner described in Example 5A, Son-androstane- 3a,1l 8-diol-l7-one 3-acetate is reacted with methanesulfonyl chloride in pyridine and the resultant product isolated and purified to give 5a-9(11)-ar1drostene-3a-oll7-one 3-acetate.

B. 9:1-bromo-5ot-androstanc3a,]IB-dioI-I7 -0ne 3-acemica-In a manner similar to that described in Example 513, 5a-9(l1)-androstene-3a-ol-17-one 3-acetate is reacted with N-bromoacctamide and perchloric acid and the resultant product isolated and purified to give 9a-bromo- 5a-androstane-3u-i1,8-diol-17-one 3-acetate.

C. 9,8,115-0xizl0-5tz-androstane- 'm ol 17 one 3-acetate.-In a manner similar to that described in Example 5C Qa-bromo-5a-androstane-3a,llfi-diol-U-one 3-acetate is reacted with potassium acetate in acetone and the resultant product isolated and purified to give 919,115- oxido-5a-androstane-3ut-ol-17-one 3-acetate.

D. 9a-fluoro-5a-andramatic-3a,I1ti-di0I-I7 one 3-acerate-In the manner described in Example 5D, 9B,11floxide-5a-androstane-3a-ol-17-one 3-acetate is reacted with hydrogen fluoride in chloroform and tetrahydrofuran and the resultant product isolated and purified to give 90:- fluoro-5a-androstane-3ix,11fl-diol-17-one B-acetate.

E. S at-chl0r0-5a-al1dr0sta'ne-3a,IIfi-di0l-17 one S-acetate.-In a manner similar to that described in Example 513 95,11,8-oxido-5a-androstane-3a-ol-l7-one B-acetate is reacted with anhydrous hydrogen chloride and the result ant product isolated and purified to give 9a-chloro-5aandrostane-3a, l lti-diol-17-onc S-acetate.

EXAMPLE 8 In a manner described in Example 1A 5a-androstane- 3a,11fi-diol-17-one 3-acetate is reacted with nitrosyl chloride in pyridine and the resultant product isolated and purified to give 5aandrostane-3rx,11B-diol-17-one 3-acetate ll-nitrite.

In a manner similar to that described in Example 1B 5ct-211ld1OSl2ll'lfi3-3ut,llfi-dlOl-l7-Ont3 B-acetate ll-nitrite in toluene solution is irradiated with a ZOO-Watt mercury lamp and the resultant product isolated and purified to give 18-nor-D-homo-5a,13(17a)-androstene 3a,11fl-dio1- 17-one 3 acetate.

EXAMPLE 9 9a-hal0gen0-18-rt0r-D-h0m0-5or-13 (1 7a -androstene 3a,]1B-di0l-1 7-one 3-acetate 9ot-fiuoro-5a-androstane-3a-1l;9diol-17-one 3-acctate is reacted with nitrosyl chloride in pyridine in a manner similar to that described in Example 1A and the resultant product isolated to give 9a-fiuoro-5a-androstane-3ot,1113- diol-l7-one 3-acetate ll-nitrite.

In a manner similar to that described in Example 13 9a-fiuoro-5a-androstane-3a,1lB-diol-17-one 3-acetate 11- nitrite in toluene solution is irradiated with a Pyrex filtered ZOO-watt mercury lamp and the resultant product isolated and purified to give 9a-fiuoro-l8-nor-Dhomo- 5A-13(l7a)-androstene-3a-1lfl-diol-17-one 3-acetate.

Similarly by following the same procedures described above 9a-chloro-5a-androstane-3a,1lB-diol-17-one 3-acetate and 9a-bromo-5ot-androstane 30;,11/8 diol 17 one 3-acetate are each reacted with nitrosyl chloride in pyridine to give respectively 9tx-chloro-5a-androstane-3a,11B- diol-17-onc S-acetatc ll-nitrite and 9ot-bromo-Sa-androstane-3a,11B-diol-17-one 3-acetate ll-nitrite which upon irradiation in toluene solution with a ZGD-watt mercury lamp yield products which are isolated and purified to give respectively 9u-chloro-18-nor-D'-homo-5a-13(17a)- androstene 3a,11fi-diol-l7-one S-acetate and 9a-bromo- 18-llOID-hOmO-50t-13(17H) androstene 3a,llfl-diol-17- one 3-acetatc.

EXAMPLE 10 5B-andr0starze-3fiJ1B-d1'0I-17-0ne 3-acctate and the 9a-ha10gen0 derivatives thereof A. .ifi-androstane-SBJ1fl-di0l-I7-one.To a stirred su pension of 2 g. of lithium aluminum hydride in 200 ml. of

armrest iii anhydrous tetrahydrofuran chilled in an ice bath is added dropwise a solution of g. of 4 pregnene-1lp,17tx,2ltriol 3,20-dione in 250 ml. of tetrahydrofuran. When the addition is complete, the ice bath is removed and the mixture is heated at reflux temperature with stirring for 2 hours. The reaction mixture is then chilled in an ice bath and a solution of 50 ml. of ethyl acetate in 100 ml. of tetrahydrofuran is added slowly, followed by the dropwise addition of a saturated aqueous solution of sodium sulfate. The organic layer is separated from the aqueous layer then filtered and concentrated in vacuo to a residue of 4-pregnene-3,115,l7a,20,21-pentol containing predominantly the 3,6-hydroxy isomer.

The total reaction product, 4-pregnene-3,l l,ti,l7e,20,2lpentol, obtained as described above, is dissolved in 500 ml. of ethyl acetate, then ml. of acetic acid is added and the mixture is reduced with hydrogen at atmospheric pressure utilizing 1 g. of platinum oxide as catalyst. When the hydrogen uptake ceases, the catalyst is filtered off and the solution concentrated in vacuo to a residue of a mixture of 5fi-pregnane-3o-116,17u,20,2l-pentol and 5a-pregnane-3,8,1l/3,17a,20,21-pentol and the Sat-hydroxy isomers thereof.

The total reaction mixture of 5-pregnane--3,l1fl,17a,20, ZI-pentol obtained in the manner described above, is dissolved in 200 ml. of hot percent aqueous acetic acid, 25 g. of sodium bismuthate is added and the mixture is heated with vigorous stirring on the steam bath for one hour. The mixture is filtered and the filtrate poured into water, the product is extracted with methylene chloride. The organic extracts are combined, washed with water, with aqueous sodium carbonate and again with water, dried over sodium sulfate then filtered through a column of Florisil with methylene chloride. The methylene chloride eluate is concentrated to a residue which is chromatographed on a partition column using toluene-propylene glycol on 500 g. of Chromosorb. Those fractions containing Sm-androstane-3a-Jlo-diold7-onc, Set-androstatue-36,11,8-diol-17-one, and 5androstanc-3a,lifi-diol- 17-one (as indicated by paper chromatography) are discarded. The remaining fractions are subjected to infrared analysis and those possessing a hydroxy group and a S-rnembered ring ketone are combined and crystallized from acetone-hexane to give SB-androstanedtllljddiol-l7-one.

B. 5 8 arzdrosmne 35,1];9 diol 17 one 3-occtate.- To a solution of mg. of 5 3-androstane-3;3,1l e-dioll7-one in 2 ml. of pyridine is added 100 mg. of acetic anhydride. The reaction mixture is allowed to stand at room temperature overnight and poured into cold dilute hydrochloric acid with stirring. The aqueous mixture is stirred for 15 minutes and the resultant solution filtered and crystallized from aqueous methanol to give fio-androstane- 3,6,l lB-diol-U-one 3-acetate.

C. 90; bromo Sfi androstnne 318,1],8 dial 17- am: 3-acetate.ln a manner similar to that described in Example 5A 5,8-androstane-3d1lfl-diol-l'I-onc 3-acetate in pyridine is reacted with methanesulfonyl chloride in chloroform and the resultant product isolated and purified to give 5o-9(1l)-androstene-3o-ol-l7-one 3-acetate.

in a manner similar to that described in Example 53 5;3-9(11)-androstene3;3-ol-l7-one 3-acetate in dioxauc reacted with N-bromoacetamide and perchloric a The resultant product is isolated and purified in the described manner to give 9oi-bronio-Sfi-androstane-Bo,ilfi-diol-l7- one S-acetate.

D. 9a-flu0ro 5B mzdrostane 3 3.1113 dz'ol I7 one 3acetatc.In a manner similar to that described in Example SC 9et-bromo-5 3-androstane-3y3,lljZ-diol-l7-one 3- acetate in acetone is reacted With potassium acetate and the resultant product isolated and purified to give 95,1 looxido-Sdandrosttine-3 B-ol-l7-0ne 3acctate.

In a manner similar to that described in Example 5 96,1lrs-oxido-Sfl-anrlrostanc-EfS-ol-l7-one 3-acctatc is reacted with hydrogen fluoride in chloroform tetrahydro EXAMPLE 1 1 i 8-!i0r-D-hc-m0-5 5-1 3 1 7a -arzdrostene-3/?, 1 1 fi-dioI-I 7-- one 3-acelale and the 9ot-hal0gen0 derivatives thereof In a manner described in Example 1A Sii-andr-ostane 3,8,11 'i-diol-i7-one is reacted with nitrosyl chloride in pyridine and the resultant product isolated and purified to give fifi-androstene-Bfi,11/8-diold7-one 3-acetate ll-nitrite.

in the manner described in Example 18 Sfi-androstane- 3,8,11,6-diold7-one 3-acetate ll-nitrite in toluene under a blanket of nitrogen is irradiated with a 200 watt mercury lamp and the resultant product isolated and purified to give l8-nor-D-homo-5,813(17a)-androstene-3,8,1lii-diol- 17-one S-acetate.

iiy following the procedure outlined above in this example 9wfluoro-5o-androstane-3B,1lfi-diol-l7-one 3-acetate, Qa-bromo-Sfi-androstane-3,B,l1 3-diol-17-one 3-acetate and 9a-chloro-SB-androstane-35,llfi-diol-17-one 3-acetate are each reacted with nitrosyl chloride to give respectively, 9ot-tluoro-SB-androstaue-Sfi,1lB-diol-U-one B-acetate 11- nitriie, 9a-bron1o-5 S-androstane-BB,11,6-diol-l7-one 3-acetate ll-nitrile, and 9n-chloro-Sfi-androstane-E 3,lld-dioll'lonc S t-acetate ll-nitrite which are then irradiated with a 200 watt mercury lamp while in a toluene solution to give respectively 9a-fluoro-1S-nor-Dhomo-Sdl3(17a)- androsteneddll/i-dio -l7-one B-acetate, 9a-bromo-lS- nor-D-homo-5B-13(17a)-androstene-3,B,1lfi-diol-l7-one 3- acctate and 9a-chloro-1Snor-D-homo-5B-l3(17a)-androstenc-3{ ,l l Mliol-li-one 3-acetate.

EXAMPLE l2 Hydrolysis of the 3-ncemrc esters of 18-:1or-D-h0m0-13 (170)-rmrfrostencs to the corresponding 3-hydr0xy clerivirit'es A. 18 nor D homo 5a 13(l7a) androstene- 3,6,llfi-diol-l7-one B-acstate (the compound of Example 1) is subjected to the action of a culture of Fiuvobncterium deii t'drogcnans (Rutgers Collection No. as follows:

The culture of the organism is prepared by propagating it in a nutrient agar medium at 30 C. for 24 to 72 hours. During incubation, the inoculated tube is exposed to light with the resultant development of a yellow pigment characteristic of the species. The developed culture is rinsed from an agar slant under sterile conditions into a sterile medium of pH 6.8 and having the following composition:

Gm. Yeast extract (Difco) 10 Potassium phosphate monobasic 4.43 Sodium phosphate dibasic 4.68

Tap Water, to 1 liter.

This culture medium has previously been autoclaved, at 15 lb. pressure, for twenty minutes to obtain aseptic conditions, and cooled. The variant is grown in the medium under constant illumination, using the visible range of the spectrum. The incubation tempcrture is main- 13 paper chromatography indicates that there is no more starting material.

The contents of the flasks are combined and extracted with methylene chloride. The extracts are concentrated and the residue is crystallized from acetone-hexane yielding 18-nor-D-horno-5a-l3(17a) androstene-BBJlfl-diol- 17-one.

B. In a similar manner, 9ot-chloro-18-norD-homo-5a- 13(17a)-androstene 35,115 diol-l7-one 3-acetate, 9abromo 18 nor-D-horno-5a-13(17a)-androstene-3fl,l1,9- dil-17-one B-acetate, 9a-fiuoro 18 nor-D-homo-e-13- (17a)-androstene-3fl,115-cliol-17-one 3-acetate (prepared as in Example 6), l8-nor-D-homo-5fi-l3(l7a)-androstene-3a,11B-diol-17-one 3-acetate (compound of Example 2) and the 9a-chloro-, 9u-brorno-, and 9a-fluoro-derivatives thereof (prepared as described in Example 6), 1S- nor-D-homo-5a-13(17a)-androstene3rx,11,8-cliol-17-one 3- acetate (compound of Example 8) and the 9zx-ChlOI'0-, 9a-brorno-, and 9a-fluoro derivatives thereof (prepared as in Example 9), 18-nor-D-homo-5/3-13(17a)-androstene-3fl,11fl-diol-17-one 3-acetate and the 9'a-chloro-, 9a-bromo-, and 9a-fluoroderivatives thereof (prepared as in Example 11) are each subjected to the action of a culture of Flavobacterium dehydrogenaizs and the resultant products isolated and purified to give respectively 90:- chloro 18 nor-D-homo-5rx-13(17a)-androstenc-3e,11 fldiol-17-one, 9a-bromo-18-nor-D-horno-5a-13(17a)-androstem-35,1 lfi-diol 17 one, Qa-fiUOI'O-IB-IIOI-D-hOmO-Sa- 13(17a) androstene-3}3,l1,8-diol-17-one, 18-nor-D-homo- 55-13(17a)-androstene-3a,11;8-diol-17-one, 9a-Ch1010-18- nor-D-homo-SB-l 3 17a) androstene-3ot,11fi-diol-17-one, 9a bromo 18 nor-D-homo-5fi-13(17a)-androstene-3a, llfl-diol 17 one, 9a-fluoro-18-nor-D-homo-5 '3-13(17a)- androstene-hdlfi-diol 17 one, l8-nor-D-homo-5a-l3- (17a) androstene-3a,ll;i'diol17-one, 9a-chloro-l8-nor- D-homo-5a-l3(l7a) androstene-3a,1lfi-diol-l'i-one, 9abromo 18 nor-D-homo-5rx-13(17a)-androstene-3a,11;8- diol-l7one, 9a-tluoro-18-nor-D-homo-5a-l 3 l7a)-androstene-3a,11lS-diol l7 one, 18-norD-homo-5fl-l3(17a)- androstene-3fl,l lfl-diol-l7-one, 9ot-chloro-18-nor-D-homo- 5fl-13(l7a)-androstene-3;3,l1fi-diol-17-one, 9a-bI0II1018- nor D homo-5;8-13(l7a)-androstene-3,8,l 1;8-dioll7-one and 9a-fiuoro-18-nor-D-homo-5B-13(17a)--androstene-3,8, 11,8-diol-17-one.

EXAMPLE 13 Preparation of II-esters 0f 18-nor-D-h0m0-13U 7a andr0stene-3J 7-di0nes A. 18 nor D homo-541430711) -andr0sIene-1];3-0I- 3,17-dione 11-acetate.To a solution of 100 mg. of 18- nor D homo-5a-13(17a)-androstene-11,6-o1-3,17-dione (the compound of Example 4) in 2 ml. of pyridine is added 100 mg. of acetic anhydride. The reaction mixture is allowed to stand at room temperature overnight then is poured into cold dilute hydrochloric acid with stirring. The aqueous mixture is stirred for minutes and the resultant solid is filtered and crystallized from aqueous methanol to give 18-nor-D-homo-13(l7a)-andr0- stene-llB-ol-3,l7-dione ll-acetate.

B. In a similar fashion, 9tx-tluoro-18-nor-D homo-5u- 13(l7a) androstene-l1;3-ol-3,l7-dione, 9oc-Ch101'0-18-1l0f- D-horno 50c 13(17a)-androstene-11B-ol-3,l7dione and 9m-bromo 18 nor-D-homo-5rx-13(17a)-androstene-11B- o1-3,17-dione are each reacted with acetic anhydride in pyridine to give 9'a-fluoro-l8-nor-D-hon1o-5a-13(17a)- androstene-llB-ol 3,17 dione 11-acetate, 9a-cl1loro-l8- nor-D-homo-5u-13(17a)-androstene-1 lfl-ol-3,17dione 11- acetate, and 9a-bromo-18-nor-D-homo-5 1-13(17a)-androstene-11B-ol-3,17-dione ll-acetate.

C. Other carboxylic acid esters and sulfonic acid esters of l8-nor-D homo-5a 13(17a) androstene-11p-ol-3J7- dione and the 9ot-fluoro, chloro, and brorno analogs there of are obtained by utilizing the above procedure and substituting anhydrides of carboxylic acids such as caproic and propionic or the acid chloride of benzoic acid or of methylsulfonic or p-toluenesulfonic acid for acetic anhydride in the above procedure to obtain the corresponding esters, e.g., 18-nor-D-h0mo-5a-13(17a) androstene-1l,8- ol-3,17-dione ll-caproate, 18-nor D homo-5a-l3(17a)- androstene-ll{3-ol-3,l7-dione ll-propionate and l8-nor- D-homo 13(17a)-androstene-1l,8-ol-3,l7-dione 1]- benzoate, 18-nor-D-hom0-5a-13(17a)-androstene-11,6-01- 3,17-dione 11 methanesulfonate, 18-IlOr-D-i101IlO-5wl3- (l7a)-androstene-11;3-ol3,17-dione 11-ptoluenesu1fonate and the 9a-fiuoro-, 9a-chloro-, and 9a-bromo-analogs thereof.

D. In a similar fashion, 18-nor-D-homo-5fi-13(17a)- androstene 1l,3-ol-3,l7 dione and the 9a-fiuoro-, 9achloro-, and 9a-bromoderivatives thereof may be reacted with acetic anhydride according to the procedure of Example 13A to give respectively 18-nor-D-homo-55- l3(l7a)-androstene 115-01317 dione ll-acetate, cfiuoro 18 nor-D-homo-Sp3-t3(17a)-androstene-11p-ol- 3,17-dione, 9a-chloro-18-nor-D-homo-5fl-l3(17a)-androstene-11fl-ol-3,l7-dione ll-acetate and 9u-bromo-l8-nor- D-.homO-5B-13 17a)-androstene-1 1,9-01-3, 17-dione 11-acetate.

Similarly, by substituting other carboxylic acid anhydrides such as propionic, or acid chlorides, such as benzoyl chloride or p-toluenesulfonyl chloride, for acetic anhydride in the above procedure there is obtained the corresponding ll-propionate, ll-benzoate, or ll-p-toluenesulfonate of 18-nor-Dhomo-5 8-13(l7aJ-androstene- Ilfl-ol 3,l7-dione and of the 9a-fiuoro-, 9a-chloro-, and 9q-bromo analogs thereof.

EXAM PLE 14 Preparation of 3-m0ri0esrcrs of 3,1IddIhydmxy-IS- nor-D-h0m0-13(1 7a) -arzdr0.rtenes One gram of 18-nor D-homo-5a13(l7a)-androstene- 3fi,11B-diol-l7-onc dissolved in 20 1111. of pyridine con taining 500 mg. of propionic anhydride and is allowed to stand at room temperature for two hours. The reac tion mixture is then poured into cold dilute hydrochloric acid with stirring. Stirring is continued for 15 minutes longer. A solid separates which is filtered and crystallized from aqueous methanol to give 18-t10I-D hOITlO-5a- 13 (17a)-androstene-3;3,1 1fi-diOl-17-O1'lfi 3-propionate.

In a similar manner, l8-nor-D-homo 5B 13(l7a)- androstene-hdlfi-diol 17 one, l8-nor-D-homo5a-l3- (17a)-androstene-3a,l lB-diol-l'i-one, 18-nor-D-homo-5B- 13(17a)-androstene-3,8,11fi-diol-17one and the 9|xfitlOIO-, 9a-chloro-, and 9a-bromo-derivatives thereof are each reacted with acetic anhydride in a manner similar to the above procedure to give respectively 18-nor-D-homo-55- 13(17a)-androstene-3,1lti-diol-l'l-one 3-acetate, 18-nor- D-homo-5a-l3(17a)-androstene-3a,115-diol-17-one 3-acetate, 18-nor-D-homo-5B-13U7a) androstene-Ilfidlfi-diol- 17-one 3-acetate and the 90c-flLl0I0-, 9a-chloro-, and 9abromo-derivatives thereof, e.g., 9a-fill0I0-l8-DOf-D-h0m0- 513-13(l7a)-andr0stene-3a,llB-diol-l7-one 3-acetate, 9w fiuoro-18-nor D homo-5:143(17a)-androstene-3a,l1 8- diol-17-one 3-acetate and 9a-fiuoro-IS-nor-D-homQ-Spl3(17a)-androstcne-3t?,11fi-diol-17-one 3-acetate.

By substituting acid anhydrides such as valeric and caprylic anhydride or benzoyl chloride for propionic anhydride in the above procedure, there is obtained the corresponding ester, i.e., the 3-valerate, 3-caprylate, and S-benzoate respectively, of 18-nor-D-homo-5a-13(17a)- androstene-Sdl1,8-dio1-17-one, 18-nor-D-homo 5,8 13 (17a) -ElI1dIOS'tIlB-3zx,l 1,6-diol-17-one, 18nor-D-homo-5a- EXAMPLE 1S 3,11-dicsters of 3,11B-dihydroxy-18-n0r-D h0rn0-13 {1 7a)- androstenes I7one diacetate.To 500 mg. of l8-nor-D-homo-5a-l3 w 100 mg. of 18 nor-D-homo-5a-l3(l7a)-androstene-35,

1lB-dio1-17-one is dissolved in 2 ml. of pyridine containing 200 mg. of acetic anhydride. The reaction mixture is left overnight at room temperature then poured into cold dilute hydrochloric acid with stirring. A solid separates which is filtered and dried to give 18-nor-D-homo- Sci-l3(l7a)-androstene-3fi,llfi-diol-l7- one diacetate.

In a similar fashion, by utilizing the procedure in the first paragraph of this example on the 3-acetates prepared in Examples 2, 6, 8, 9, and 11, or by utilizing the alternative procedure described above on the corresponding 3,11-dihydroxy-compounds prepared in Example 12, there are obtained the corresponding 3,11-diacetate esters.

By substituting benzoyl chloride or the anhydride of another alkanoic acid such as valeric and caprylic for acetic anhydride in the above alternate procedure there is obtained the corresponding 3,1l-dibenzoate or 3,11- divalerate and 3,l1-dicaprylate of the respective 18-nor- D-homo-l3(l7a)-androstene-3,l1ti-diol-17 h one starting steroid.

B. Mixed esters-To 100 mg. of l8-nor-D-homo-5al3(l7a)-androstene-3B,llfi-diol-17=one 3 acetate (the compound of Example 1) in 2 ml. of pyridine is added 50 mg. of caproic anhydride. The mixture is allowed to stand at room temperature for six hours, then poured into dilute aqueous hydrochloric acid with stirring. The result- I ant solid is filtered and dried to give l8-nor-D-homo-5a- 13(l7a)-androstene-3fi,l1;3-diol 17 one 3-acetate llcaproate.

In a similar fashion, 18-nor-D-homo-l3(17a)-androstem-3,8,11,8-diol-lT-one 3 benzoate (prepared as described in Example 14) is reacted with acetic anhydride in pyridine overnight. The resultant product is isolated to give IS-nor-D-homo-M-IS(17a)-androstene 35,116: diol-l7-one 3-benzoate ll acetate.

In like manner, by substituting other l8-nor-D-homothat various combinations of 3,1l-mixed esters may be I obtained.

It is to be understood, that the invention is not to be limited to the exact details of operation or exact compounds shown or described as obvious modifications and equivalents will be apparent to one skilled in the art. P

The invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of 3-Z-9oi-X-llp-Y-17-keto-l8-nor-D-homo-13(17a) dehyi ii dro-ia-androstane and 3-Z-9ix-Xl lp-Y-l7-keto-l8-non-D- homo-l3(17a)-dehydro-5fi -androstane wherein Z is a member selected from the group consisting of keto; (H,BOR') and (l-LaOR'), R being a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic acids and aryl carboxylic acids; X is a member selected from the roup consisting of hydrogen, fluorine, chlorine, and bromine; and Y is a member selected from the group consisting of hydroxy and OR, R being an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic acids and aryl carboxylic acids.

2. 3-OR-l l e-hydroxy-l7-keto-l8-norD-homo-13(17a)- dehydroandrostane having saturated A, B, and C-rings and a hydrogen atom at C-S, said hydrogen atom being in one of the configurations selected from the group consisting of u and ,6, wherein R is an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic acids and aryl carboxylic acids.

3. l1BOR-l8-nor-D-homo-l3(17a)-androstene 3,17- dione having saturated A, B, and C-rings and a hydrogen atom at C-5, said hydrogen atom being in one of the configurations selected from the group consisting of 5a: and 5,8, and wherein R is an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic acids and aryl carboxylic acids.

4. 3,11fi-di(OR)-17-keto-1S-nor-D-homo-13(17a) dehydroandrostane having saturated A, B, and C-rings and a hydrogen atom at C-5, said hydrogen atom being in one of the configurations selected from the group consisting of 5a and 55, wherein R is an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic acids and aryl carboxylic acids.

5. l8-nor-D-homo-5a-l3(l7a)-androstcne-lIdol-3,17- dione.

6. 18-nor-D-homo-5fi-l3 17a)-androstene-l Idol-3,17- dione.

7. 18-11OP-D-hDH10'-5CL-13( 17a)-androstene-3,B,llfi-diol- 17-one.

8. 18-nor-D-homo-5u-l3(17a)-androstene-3fi,1lfl-dioll7-one I i-acetate.

9. l8-nor-D-homo-Su-l3(17a)-androstcne-3B,l1,B-dioll7-one diacetate.

10. 9a-fill0f0-l8-I10r-D-hOmO-5a-l3(17B.) androstene- 35,11,8-diol-17-one.

11. 18-nor-D-homo-5a-13(17a)-androstene-3e,1 LB-dioll7-one.

12. 18-nor-D-homo-Sp-13(17a)-androstene-3e,1lp-dioll7-one.

13. l8-nor-D-homo-SB-13(17a)-androstene-3,8,ll,B-diol- 17-one.

14. In the process of preparing a compound selected from the group consisting of 3-Z-9OL-X-11fi-Y-17k6t()"18' nor-D-homo-l3(17a)-dehydro-5a-androstane and 3-2-9- X-llp-Y-l7-keto-l8-nor-D-horno-l3(l7a)-dehydro 5pandrostane, wherein Z is a member selected from the group consisting of keto, (H.5OR') and H,aOR'), R being a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of alltanoic acids and aryl carboxylic acids;

X is a member selected from the group consisting of hydrogen, fluorine, chlorine, and bromine; and

Y is a member selected from the group consisting of hydroxy and OR, R being an acid radical selected from the group consisting of methanesulfonic acid, p-tolucne-sulfonic acid and a hydrocarbon carboxyl- 3,194,831 17 18 ic acid having up to 8 carbon atoms selected from References Cited by the Examiner the group consisting of alkanoic acids and aryl car- UNITED STATES PATENTS boxylic acids;

the steps which comprise irradiating an ll-nitrite ester fi i g 'g g g g of a steroid selected from the group consisting of 5 2847457 8/58 Johnson et a1 260 188 3-Z-9a-X-11B-hydroxy-l7-keto-5a androstane and 2936276 5/50 chalkey 204 158 3-Z-9a-X-11B-hydroxy-17-keto-5fl-androstane where- 2,941,934 6/60 Anspon et a] in Z and X are as hereinabove defined, in an inert 3.024271 3 M2 Amiard et a1 260 586 solvent, with ultraviolet radiation having a wave length greater than about 3000 A. and less than about 10 OTHER REFERENCES 4400 A., said radiation including an absorption band Johnson et LACS 1 PP- 63396347 of said ll-nitrite radical, and isolating the thereby formed 3-Z-9a-X-1lfl-hydroxy-l7-keto-18 nor D- CHARLES PARKER Pnmary Exammer homo-13(17a)-dehydro) androstane. JOSEPH P. BRUST. Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-Z-9A-X-11B-Y-17-KETO-18-NOR-D-HOMO-13 (17A) - DEHYDRO-5A-ANDROSTANE AND 3-Z-9A-X-11B-Y-17-KETO-18-NOR-DHOMO-13 (17A)-DEHYDRO-5B-ANDROSTANE WHEREIN Z IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF KETO; (H,BOR'') AND (H,AOR''), R'' BEING A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND AN ACYL RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF ALKANOIC ACIDS AND ARYL CARBOXYLIC ACIDS; X IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, FLUORINE, CHLORINE, AND BROMINE; AND Y IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROXY AND OR, R BEING AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF ALKANOIC ACIDS AND ARYL CARBOXYLIC ACIDS. 